Insulin Resistance in the brain

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Over time, if you’re developing insulin resistance of the body, you’re also developing insulin resistance of the brain. Depending on the individual, this process of developing insulin resistance can focus primarily in the body or in the brain. Some people with insulin resistance will develop Alzheimer’s Disease, some heart disease, some Type 2 diabetes, some Cancer, some Polycystic Ovarian syndrome, etc. Why insulin resistance manifests in different ways is unclear, but it likely depends on an individual’s genetics, lifestyle, environment, and other factors.

Nevertheless, there is a clear connection between insulin resistance and Alzheimer’s, so much so that in 2008 the term Type 3 Diabetes was coined as a descriptive way of referring to Alzheimer’s Disease. Alzheimer's Disease Is Type 3 Diabetes–Evidence Reviewed (Suzanne M. de la Monte, Jack R. Wands, 2008) Since 2008, there has been additional research strengthening this link between Alzheimer’s disease (AD) and insulin resistance.

Insulin in a healthy body

Let’s review how insulin works in a normal, healthy body:

  1. Food, particularly sugar and starches are broken down into blood glucose (see Blood Sugar).
  2. The body prefers to keep glucose in the blood regulated to a near constant level (metabolic homeostasis), which is insulin’s function.
  3. When blood glucose rises after a meal, the pancreas releases insulin to escort the glucose out of the bloodstream into cells where it’s needed. Insulin does this by binding to receptors on the surfaces of the body’s cells. The insulin is the “key” that fits in to the receptor to “unlock” the cell and let glucose in where it is needed.
  4. Insulin plays a much different role in the brain; it is not the driving force to bring glucose into neurons, but instead seems to play more of a signaling role.

Insulin resistance in the body

If a person eats a sugary/carby meal, the body will be flooded with glucose, more than it needs. The body pumps out lots of insulin to handle all this glucose, storing it (in the form of fat), in order to get the blood sugar levels back to normal.

Over time, with lots of sugary/carby meals and snacks, this process of excess insulin production causes damage to the body: the receptors become desensitized, the insulin receptors become numb to insulin. The insulin receptors also downregulate, In other words they become fewer in number. Fat is supposed to be stored in fat cells, called adipocytes, but in most people, this is a finite capacity. When the fat cells have become overfilled they can’t get enough oxygen and they become inflamed. When there’s no more room in the fat cells, the body then looks for other places to store fat, including where fat was never meant to go: the abdominal cavity (visceral fat), other organs (liver, pancreas, kidneys), and muscle. This ectopic fat (fat stored in areas besides fat cells) interferes with cellular functions and results in organ dysfunction. Like a splinter, ectopic fat is constantly annoying/stressing the body.

A condition commonly associated with persistent high insulin is Non-Alcoholic Fatty Liver disease (NAFLD). A fatty liver is insulin resistant, so it’s not regulated by insulin appropriately, it keeps pumping out glucose (gluconeogenesis) even though the body doesn’t need glucose, thus exacerbating the problem. When the pancreas is overtaxed but able to pump out enough insulin to maintain a relatively even and low level of glucose, that’s insulin resistance in the body (simplified). Insulin resistance develops over years. Without intervention, insulin resistance ultimately becomes Type 2 Diabetes. With Type 2 Diabetes, insulin no longer works well in the body and blood sugar levels stay high. A blood sugar test alone cannot determine if a person is insulin resistant, see Blood Sugar

Type 2 diabetes is just one possible end result of insulin resistance. To be clear, while there is a strong relationship, one can develop Type 2 diabetes and never get Alzheimer’s. Conversely, one can have Alzheimer’s and not diabetes. One thing is clear, however, insulin resistance in the brain occurs in Alzheimer’s patients, regardless of if there is insulin resistance elsewhere in the body.

Insulin resistance in the brain

Insulin resistance in the brain is different than insulin resistance in the body.

In the body, glucose is escorted into cells through transporters called Glucose Transporter 4 (GLUT-4), these are regulated by insulin. But in the brain, blood vessel walls form the first layer of much of the Blood Brain Barrier (BBB). The Blood Brain Barrier adds a layer of protection for the precious brain. The endothelial cells of the blood vessels fit together tightly (tight junctions) so substances such as disease-causing pathogens and toxins cannot pass out of the bloodstream into the brain.

But the brain doesn’t want to impair glucose from entering. Unlike in the body, on the blood brain barrier there are what’s called Glucose transporter 1 (GLUT-1), they let glucose into the brain without being regulated by insulin. The concentration of glucose within the brain is linearly related to the concentration of glucose within the body. The GLUT-1 receptor can change in density (number of) in the BBB with changes in Glucose levels over time. More GLUT-1 transporters means closer glucose concentration in Central Nervous System (CNS) to peripheral (body) blood concentration.

The brain wants unimpaired glucose passage, because the brain needs fuel and lots of it. The brain uses more energy than any other human organ. The brain constitutes only 3% of the body's mass, but uses approximately 25% of the body's energy and it needs energy 24 hours a day.

Once past the BBB, glucose uses another Glucose transporter (GLUT-3) to enter neurons. This transporter actually attracts glucose and like GLUT-1, is independent of insulin. This means that even at low concentrations, neurons can still get glucose. Also like GLUT-1, GLUT-3 can change in density in the neuron cell wall over time.

The brain only makes up 3% of a body's weight, but uses up 25% of the body's energy and it needs energy 24 hours a day.

The human brain developed over millions of years under conditions that aren’t typified by today’s modern lifestyle of abundant food filled with sugar and simple carbohydrates. Rather, the brain developed under conditions of periodic food paucity, virtually no sugar, and limited high-glycemic foods. Given that past history, the brain doesn’t want to restrict access to glucose. While the brain can burn ketones and ketones burn cleaner and more efficiently, see Ketosis and Ketogenic Diet there are some cells in the brain that can only burn glucose. The brain must have glucose.

Most of the brain’s energy consumption goes toward sustaining neurons. Because of these non-insulin dependent GLUT-1 receptors on the blood brain barrier, glucose freely flows into the brain, but with modern diets these glucose levels can be exceptionally high.

The brain needs insulin

Even though the brain does not use insulin to bring glucose into neurons, the brain is dense with insulin receptors, particularly in:

  • Hippocampus (the brain’s memory center)
  • Amygdala (mood)
  • Cortex (cognition/executive function)

The regional concentration of Insulin Receptors in the Hippocampus suggest insulin may play a role in memory, and that learning itself could influence the density / concentration of Insulin Receptors. While insulin does not help bring glucose into neurons, there is some evidence that it may still affect cerebral energy metabolism. Insulin may be involved in controlling the localized concentration of GLUTs. In addition, insulin-responsive GLUT-4 and GLUT-8 are also located in the brain, though at lower levels. The understanding of cerebral glucose metabolism is still basic, but expanding. Insulin has also been shown to control levels of some neurotransmitters. Disruption of insulin signaling (insulin resistance) can lead to neurodegenerative disorders like AD. Insulin resistance happens when insulin binding with receptors has less effect. Normally, Insulin Resistance is thought of as a decreased ability to bring glucose into cells, but it can also lead to a decreased signaling ability. Prolonged peripheral glucose elevation can lead to downregulation of GLUT-1 transporters at the BBB, lowering the amount of insulin that can enter the brain. Chronic high levels of insulin can impair learning and can result in changes to brain structure and volume and reduced brain glucose metabolism.

Insulin resistance and AD share common pathologies, supporting the notion that insulin resistance can lead to AD. These similarities include inflamation, dyslipidemia, amyloidogenesis and mitochondrial dysfunction.

Cerebral Glucose Hypometabolism results from Insulin Resistance

Insulin resistance results in slowed glucose processing in the brain

Too much glucose without the requisite insulin results in Cerebral Glucose Hypometabolism, which means slow glucose metabolism. This slow glucose metabolism is likely: (1) contributing to Alzheimer’s development and (2) a consequence of Alzheimer’s Disease. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. (SC Cunnane, et al, 2016)

In other words, there’s a vicious cycle: the slowed brain glucose uptake (hypometabolism) leads to chronic brain energy deprivation, that in turn deteriorates the neuronal function, which further diminishes the demand for glucose thereby furthering cognitive decline. This hypometabolism may begin 30 or more years before the onset of AD especially in individuals with ApoE4 genotype or maternal family history of Alzheimer's Disease.

The hippocampus, where Alzheimer's Disease originates, is highly dependent on insulin and glucose

While this cerebral glucose hypometabolism continues for decades before Alzheimer’s disease manifests, it’s not until glucose processing has diminished 15% to 25% that cognitive symptoms become evident. So by the time Alzheimer’s is diagnosed, there’s already damage in the brain. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. (SC Cunnane, et al, 2016). This is a process that precedes Alzheimer’s Disease by decades Effects of ketone bodies in Alzheimer's disease in relation to neural hypometabolism, β‐amyloid toxicity, and astrocyte function (L Hertz, et al, 2015)

In particular there is the hippocampus of the brain, where memory and learning takes place, and where Alzheimer's Disease begins. The hippocampus has a high demand for glucose Insulin Resistance in Alzheimer's Disease (KT Dineley et al, 2014) as well as the highest density of insulin receptors in the brain.Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome, (B. Kim and E. Feldman, 2015) The hippocampus is one of only two places in the brain where neurons are generated, brand new baby nerve cells. Nutrition, adult hippocampal neurogenesis and mental health ((M S A Zainuddin and e Thure, 2012) So this is a very special, metabolically active place in the brain. It requires a lot of insulin and glucose.

By the time cognitive impairment symptoms manifest, the hippocampus has shrunk 10% and Glucose Processing has gone down 15% to 25%.

The hippocampus is so dependent on glucose that it has GLUT-3 and GLUT-4 receptors. While GLUT-3 receptors are not insulin dependent, GLUT-4 are insulin dependent. When insulin stimulates a GLUT-4 receptor, the GLUT-4 receptor allows an extra boost of glucose into the cells when it needed. But if you don’t have enough insulin, you won’t be able to charge your hippocampus when needed. Insulin Regulates Brain Function, but How Does It Get There? (S M Gray, et al, 2014) This means that if the blood brain barrier is insulin resistant, there isn’t enough insulin getting to the hippocampus for it to function adequately. This leads to hippocampal atrophy and by the time cognitive deficits are noticed, the hippocampus has already shrunk 10%.

While insulin resistance in the brain does generally correlate with insulin resistance in the body, if you want to know for sure that you have slowed brain glucose uptake, you can get a PET scan of the brain that actually visualizes how the brain is processing glucose. FDG PET (Fludeoxyglucose Positron Emission Ttomography) can be used for the assessment of glucose metabolism in the heart, lungs, and the brain.

Other ways insulin influences the brain/Alzheimer's Disease

Amyloid Plaque

Amyloid plaque develops when fragments of a protein called beta-amyloids (Aβ) clump together. A single molecule beta-amyloid fragment is toxic to a neuron. When the fragments start to clump up, they destroy the synapses of the neuron. Synapses are very important, they allow one cell to communicate with the other.

Insulin helps prevent plaques and tangles

People with Alzheimer’s tend to have large amounts of amyloid plaques particularly in the hippocampus, but studies show that neuronal damage can occur before the clumps of beta-amyloids form larger plaques. Diet, nutrients and metabolism: cogs in the wheel driving Alzheimer's disease pathology? (R Creegan, 2015)

Neurofibrillary tangles

In the long stretch of the neuron are lines of microtubules. They support the structure of the nerve and serve as a transport system. The microtubules need to be lined up to work properly, if they become tangled the cell can’t send messages properly or function properly. The tau protein sits on the microtubule to keep them nice and straight.

Insulin works on the tau protein, it regulates its phosphorylation. If there is inadequate insulin the tau detaches from the microtubules and leaves those microtubules. Without tau, the microtubules don’t stay aligned, they become twisted, collapse and become neurofibrillary tangles.

Insulin resistance leads to neurotoxic excess glucose

As discussed above, when the brain becomes insulin resistant a situation where unlimited glucose has been allowed in the brain develops but with slowed glucose processing the brain can't use it all, so the brain is swimming in a sea of glucose that it is unable to use and the excess glucose then becomes damaging to the brain.

This paper Glucose neurotoxicity (DR Tomlinson and NJ Gardiner, 2008) discusses how neuronal cellular damage can occur under conditions of excess glucose exposure:

  • Depletes natural antioxidant reserves, glutathione, the body’s own antioxidant
  • Promotes damaging free radical formation, these are violent molecules that create collateral damage, wrecking havoc with your DNA and more
  • Generates Advanced Glycation End Products (AGEs), sticky dysfunctional proteins
  • Slows nerve cell conduction speed
  • Reduces growth factor activity, growth factor keeps cells healthy and robust and thriving

Why is it important for ApoE ε4s?

Alzheimer's patients carrying ApoE4 show a more severe medial temporal hypometabolism than matched ApoE4‐negative patients in spite of lower global amyloid burden. From Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients (Lehmann et al. 2014):

Conclusions: ApoE4+ AD patients showed lower global amyloid burden and greater medial temporal hypometabolism compared with matched ApoE4- patients. These findings suggest that ApoE4 may increase susceptibility to molecular pathology and modulate the anatomic pattern of neurodegeneration in AD.

While glucose metabolism decreases in healthy aging, the decrease is more pronounced in ApoEε4s, even late‐middle‐aged healthy ApoE4 carriers. From Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. (Reiman et al. 2005).:

We previously found that cognitively normal late-middle-aged APOE ε4 carriers have abnormally low CMRgl [Cerebral Metabolic rate for glucose] in the same brain regions as patients with probable Alzheimer's dementia. …we now find that ε4 gene dose is correlated with lower CMRgl in each of these brain regions.

Strategies to Lower Insulin Resistance

Insulin Resistance can be reversed. While very fragile, the hippocampus is also very “plastic” in other words it has the ability to CHANGE. In this video presentation AHS16 - Dale Bredesen - ApoE4 Mechanistics Dr Bredesen relays a story of an ApoE ε4/4 who experienced a dramatic increase in hippocampal volume as a result of following his protocol. See Bredesen Protocol. Of course reducing insulin resistance is only one component of Dr Bredesen's protocol, nevertheless, such stories provide tremendous hope that damage can be reversed.

For specific strategies on reversing insulin resistance, see Strategies to Lower Insulin Resistance from the main Insulin Resistance Wiki page.

A deeper dive into the science

Not a complete list.

A Systematic Review of Glucose Transport Alterations in Alzheimer's Disease (Natalia Kyrtata1 et al, 20 May 2021)

Alzheimer's disease (AD) is characterized by cerebral glucose hypometabolism. Hypometabolism may be partly due to reduced glucose transport at the blood-brain barrier (BBB) and across astrocytic and neuronal cell membranes. Glucose transporters (GLUTs) are integral membrane proteins responsible for moving glucose from the bloodstream to parenchymal cells where it is metabolized, and evidence indicates vascular and non-vascular GLUTs are altered in AD brains, a process which could starve the brain of glucose and accelerate cognitive decline. Here we review the literature on glucose transport alterations in AD from human and rodent studies.

Inflamm-Aging and Brain Insulin Resistance: New Insights and Role of Life-style Strategies on Cognitive and Social Determinants in Aging and Neurodegeneration (Yulia Komleva, et al. 14 Jan 2021)

The purpose of this review is to discuss current knowledge in the interdisciplinary field of geroscience—immunosenescence, inflamm-aging, and metainflammation—which makes a significant contribution to aging. A substantial part of the review is devoted to frontiers in the brain insulin resistance in relation to neuroinflammation. In addition, we summarize new data on potential mechanisms of calorie restriction that influence as a lifestyle intervention on the social brain. This knowledge can be used to initiate successful aging and slow the onset of neurodegenerative diseases.

(bold face added to quote for emphasis)

In this review article, numerous studies are examined concerning the effects of obesity and Type 2 Diabetes in cognitive loss thus reinforcing the concept of Alzheimer's as Type 3 Diabetes. The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer’s Dementia (J Folch, et al. 6 Sept 2019)

From Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and alzheimer’s disease (E Blázquez, et al. 9 Oct 2014):

Although the control of peripheral glucose homeostasis is one of the main functions of insulin, its action on the brain is now also being studied carefully, as it is considered an insulin-sensitive organ because insulin receptors (IR) and their signal transduction pathways have been identified in several regions of the brain that mediate important physiological effects on this organ, such as neuronal development, glucoregulation, feeding behavior, and body weight, as well as cognitive processes, including attention, executive functioning, learning, and memory (1).

And this, Insulin Regulates Brain Function, but How Does It Get There? (S M Gray, Dec 2104):

Accumulating information suggests several significant roles for insulin action in the brain. Here, we briefly review selected studies that provoke exploration of this emerging field.

Glucose hypometabolism in the brain may indicate a risk for future development or worsening of dementia. Relationship between imaging biomarkers, age, progression and symptom severity in Alzheimer's disease. (J Dukart et al. 26 Jul 2013)

Reduced glucose metabolism can be demonstrated not only in ApoE4 carriers but also in other persons at risk for developing Alzheimer's disease decades before the onset of the disease. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer's disease (L Mosconi et al. 26 Mar 2009)

Mitochondrial DNA is inherited maternally in humans and brain glucose metabolism is lower in the elderly with a maternal family history of Alzheimer's disease. Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. (L Mosconi et al. 27 Nov 2007)